Levodopa partially rescues microglial numerical, morphological, and phagolysosomal alterations in a monkey model of Parkinson’s disease - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Brain, Behavior, and Immunity Année : 2020

Levodopa partially rescues microglial numerical, morphological, and phagolysosomal alterations in a monkey model of Parkinson’s disease

Résumé

Parkinson's disease (PD) is the most common neurodegenerative motor disorder. The mechanisms underlying the onset and progression of Levodopa (L-Dopa)-induced dyskinesia (LID) during PD treatment remain elusive. Emerging evidence implicates functional modification of microglia in the development of LID. Thus, understanding the link between microglia and the development of LID may provide the knowledge required to preserve or promote beneficial microglial functions, even during a prolonged L-Dopa treatment. To provide novel insights into microglial functional alterations in PD pathophysiology, we characterized their density, morphology, ultrastructure, and degradation activity in the sensorimotor functional territory of the putamen, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cynomolgus monkeys. A subset of MPTP monkeys was treated orally with L-Dopa and developed LID similar to PD patients. Using a combination of light, confocal and transmission electron microscopy, our quantitative analyses revealed alterations of microglial density, morphology and phagolysosomal activity following MPTP intoxication that were partially normalized with L-Dopa treatment. In particular, microglial density, cell body and arborization areas were increased in the MPTP monkeys, whereas L-Dopa-treated MPTP animals presented a microglial phenotype similar to the control animals. At the ultrastructural level, microglia did not differ between groups in their markers of cellular stress or aging. Nevertheless, microglia from the MPTP monkeys displayed reduced numbers of endosomes, compared with control animals, that remained lower after L-Dopa treatment. Microglia from MPTP monkeys treated with L-Dopa also had increased numbers of primary lysosomes compared with non-treated MPTP animals, while secondary and tertiary lysosomes remained unchanged. Moreover, a decrease microglial immunoreactivity for CD68, considered a marker of phagocytosis and lysosomal activity, was measured in the MPTP monkeys treated with L-Dopa, compared with non-treated MPTP animals. Taken together, these findings revealed significant changes in microglia during PD pathophysiology that were partially rescued by L-Dopa treatment. Albeit, this L-Dopa treatment conferred phagolysosomal insufficiency on microglia in the dyskinetic Parkinsonian monkeys.

Domaines

Neurobiologie
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Dates et versions

hal-02986878 , version 1 (03-11-2020)

Identifiants

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Cynthia Lecours, Marie-Kim St-Pierre, Katherine Picard, Maude Bordeleau, Melanie Bourque, et al.. Levodopa partially rescues microglial numerical, morphological, and phagolysosomal alterations in a monkey model of Parkinson’s disease. Brain, Behavior, and Immunity, 2020, 90, pp.81-96. ⟨10.1016/j.bbi.2020.07.044⟩. ⟨hal-02986878⟩
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